Process and intermediates for preparing emtricitabine

ABSTRACT

A process is disclosed for the stereo-selective preparation of emtricitabine, which allows the desired product to be obtained in good yield and without the use of chromatographic techniques. The process for the production of emtricitabine of the formula (Ia) 
                         
is characterized by the formation and isolation of intermediate compounds of formula (XIa)
 
                         
in salified form. Emtricitabine is a known antiviral drug.

The present invention relates to a novel process for preparingemtricitabine, and more particularly a process for preparingemtricitabine characterized by the formation and isolation ofintermediate compounds in salified form.

Emtricitabine is a known antiviral drug of formula

also known under the trade name Coviracil® or FTC (Merck Index, Ed.2001, No. 3597).

The compound, as illustrated in FIG. Ia, is the cis enantiomer havingthe 2R, 5S absolute configuration, and its chemical name is4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-one (CAS).The other optical isomers, i.e. the cis 2S, 5R enantiomer (Ib) and thetrans enantiomers 2S, 5S (Ic) and 2R, 5R (Id), have lower therapeuticactivity and are therefore found to be of reduced interest inapplication.

EP 0 526 253 A1 discloses Emtricitabine, salts thereof and the use inthe treatment of viral infections.

Various routes for synthesizing emtricitabine are described in theliterature.

For example, in international patent application WO 92/14743 (EmoryUniversity), the racemic mixture of cis isomers is prepared via standardreactions and by resolution, mainly enzymatic resolution, gives thedesired 2R, 5S enantiomer.

Stereoselective synthetic routes were subsequently developed, which, bymeans of the use of chiral auxiliaries such as menthol, allow thedesired stereochemistry to be induced and allow emtricitabine to beobtained directly as a single enantiomer. US patent U.S. Pat. No.5,696,254 (BioChem Pharma Inc.) illustrates just this type of syntheticapproach, applied to the synthesis of emtricitabine, as shown, forexample, in Scheme 2B (columns 13 and 14) below:

In this scheme, the trans oxathiolane is prepared (step 1, VIII) which,when acetylated (step 2, IX) and condensed with 1-menthol, leads to themixture of intermediate diastereoisomers (step 3, X). The desireddiastereoisomer is isolated by fractional crystallization (step 4) andcoupled with silylated 5-fluorocytosine (III) (step 5), leading to thederivative XI (which is referred to hereinbelow as XIa), which, finally,by reductive removal of the chiral auxiliary (step 6), givesemtricitabine (right-hand columns 15-16, erroneously represented withinversion of configuration in position 5 of the oxathiolane).

The chiral auxiliary used is 1-menthol (II), the chiral centres of whichhave the 1′R, 2′S, 5′R absolute configuration, as illustrated below:

However, in the experimental section of the patent, discrepancies areobserved relating to the stereochemistry of the intermediates used toobtain emtricitabine.

In fact, Example 21 (column 43) correctly asserts that to prepareemtricitabine, the formula of which is clearly given at the start ofthat example, the final reduction should be performed on the compound(1′R, 2′S, 5′R)-menthyl5S-(5″-fluorocytosin-1-yl)-1,3-oxathiolane-2R-carboxylate—i.e. onintermediate XIa of scheme 2B above—as illustrated below:

The correct stereochemistry of this sequence, i.e. the use of L-mentholto induce the desired chirality corresponding to emtricitabine, wasconfirmed experimentally by us and subsequently reinforced as describedin U.S. Pat. No. 6,051,709 (Glaxo), which will be discussed later.

In the experimental section of U.S. Pat. No. 5,696,254 (BioChem PharmaInc.) the preparation of the desired intermediate XIa (having the 1′R,2′S, 5′R chirality on the menthol and the 2R, 5S chirality on theoxathiolane) does not, however, appear, since Example 18 relates to thederivative XI inverted on the oxathiolane (XIb, 1′R, 2′S, 5′R-2S, 5R),which is thus unsuitable for producing emtricitabine, whereas Example 19relates to the derivative XI inverted on the menthol (XIc, 1′S, 2′R,5′S-R2,5S).

Also, U.S. Pat. No. 6,051,709 (Glaxo), mentioned above, describes astereoselective process for the synthesis of cis nucleosides, thisprocess differing from the above process essentially by the use ofleaving groups (L) other than acetate—such as halo, cyano orsulphonate—in the coupling reaction of the intermediate X with theactivated 5-fluorocytosine III.

However, the experimental illustration is limited to the preparation ofthe non-fluoro analogue of emtricitabine, known as lamivudine (MerckIndex, Ed. 2001, No. 5367), as illustrated in scheme 1, columns 9-10,without any indication regarding the actual process yields. Example 1describes the preparation of 5-hydroxyoxathiolane required by reacting1-menthyl glyoxalate and dithianediol (part a, column 10), and thesubsequent formation of the chloro derivative (part b, column 10) andits coupling reaction with cytosine silylate (last paragraph, column10—first paragraph, column 11). The resulting product, whichprecipitates from the reaction medium, is recovered by simple filtrationand subjected to reductive removal of the chiral auxiliary to give thecrude lamivudine, which is purified, not by direct crystallization ofthe base but of the salified form, in particular of the salicylate. Itis obvious that, by this procedure, a subsequent basic treatment will benecessary to release the lamivudine base from its salt.

This procedure, which does not appear to present any particularimplementation difficulties in the case of lamivudine, becomes entirelyinapplicable when used for the preparation of emtricitabine.

Specifically, we have been able to verify experimentally that theproduct XIa, resulting from the coupling reaction of the activated5-fluorocytosine III with the appropriate acetate X (scheme 2B of U.S.Pat. No. 5,696,254) or with the corresponding analogue of formula

containing another leaving group (L) instead of acetate (U.S. Pat. No.6,051,709), is not a filterable solid at all as in the case oflamivudine, but a gel that is inseparable from its mother liquors bysimple filtration, and can be purified only by chromatography.

The entire stereoselective synthesis discussed hereinabove, when appliedto emtricitabine, thus becomes difficult to implement industrially onaccount of the problems of isolation and purification of the keyintermediate XIa.

We have now found a novel process that may be applied industrially forthe stereo-selective preparation of emtricitabine, which allows thedesired product to be obtained in good yield and without the use ofchromatographic techniques, which are particularly disadvantageous froma practical point of view.

One subject of the present invention is thus a process for preparingemtricitabine of formula

which comprises the salification reaction of the intermediate compoundof formula

dissolved in a suitable solvent, by treatment with organic or mineralacids to give the corresponding salt, which is insoluble or partiallyinsoluble in the said solvent, in readily isolable solid form. Thesesalts are not known in the literature.

The intermediate compound of formula XIa may be prepared by applying oneof the methods discussed previously, for example by condensing theintermediate X (acetate) with the activated 5-fluorocytosine III, byanalogy with the description given in U.S. Pat. No. 5,696,254 (Examples18 and 19, in which the intermediates XIb and XIc are preparedrespectively) and as illustrated below:

or as shown in U.S. Pat. No. 6,051,709, via the same coupling reaction,in which other leaving groups L (VII) are used instead of acetate:

In this case, the stereochemistry of the carbon in position 5 of theoxathiolane ring of compound VII may vary depending on the type ofleaving group and on the mechanism of the nucleophilic substitutionreaction, as is well known to those skilled in the art, and will beappropriately selected to obtain the correct chirality of compound XIa(5S).

The condensation reaction now illustrated may thus be generallyrepresented by the following scheme:

in which the group LG represents any leaving group, provided that it issuitable for giving the condensation reaction under consideration.

Preferably, LG is chosen from acetate, halo, cyano, optionallyhalogenated alkylsulphonates, or arylsulphonates, such as, for example,chloro, bromo, iodo, methanesulphonate, triflate, tosylate andbenzenesulphonate, and even more preferably from chloro and acetate.

Compound of formula VI may generally be prepared as described in theabovementioned prior art or according to standard reactions forconversion of the OH group of the2′S-isopropyl-5′R-methyl-1′R-cyclohexyl ester of (2R,5R)-5-hydroxy[1,3]oxathiolane-2-carboxylic acid V (described in U.S.Pat. No. 6,051,709, Example 1a), into the appropriate leaving group LGaccording to the scheme:

In the condensation reaction illustrated above, the 5-fluorocytosine IIImay be activated under the conditions described in U.S. Pat. No.5,696,254 and U.S. Pat. No. 6,051,709 or using other silylatingconditions, for example by treatment with trialkylsilyl halides such astrimethylsilyl chloride, or with mixtures of silylating agents in thepresence of catalysts, such as ammonium sulphate, and condensed with theappropriate intermediate VI to give the desired compound XIa.

Another subject of the present invention is thus a process for preparingemtricitabine, characterized by the formation of the salt describedabove, which further comprises the condensation reaction between5-fluorocytosine of formula

in suitably activated form, and the compound of formula

in which LG represents a leaving group chosen from acetate, halo, cyano,optionally halogenated alkylsulphonates, or arylsulphonates, to give thecompound of formula XIa.

We have verified experimentally that, independently of the route ofpreparation, compound XIa does not separate out from the reactionmedium, either by addition of hexane, as takes place, however, in thecase of the non-fluoro analogue (Example 1, column 11, lines 9-11), orby centrifugation, as for the diastereoisomers XIb and XIc (Examples 1and 19, U.S. Pat. No. 5,696,254), but rather is in the form of anunfilterable gel.

According to the present invention, the said crude intermediate XIa,obtained after working up the reaction mixture under standardconditions, is dissolved in a suitable solvent and subjected tosalification, to give an insoluble or partially insoluble salt ofcompound XIa in readily isolable solid form.

The expression “readily isolable solid form” means an amorphous orcrystalline, preferably crystalline, solid which separates out cleanlyfrom the reaction mixture without including significant amounts ofsolvent or impurities, and which is then easily isolable by filtrationor via similar common techniques.

The solvent used in the salification reaction must be capable of readilydissolving the intermediate XIa and not its salt, this salt generallyprecipitating spontaneously from the medium.

Suitable solvents are generally alcohols, such as methanol, ethanol andisopropanol, hydrocarbons such as toluene, esters such as ethyl acetate,propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate,and ethers such as tetrahydrofuran and dioxane, chlorinated solventssuch as methylene chloride, or mixtures of these solvents, preferablyalcohols, esters or ethers or mixtures thereof, even more preferablymethanol, isopropanol and ethyl acetate.

Acids that may be used are generally organic acids, for instance mono-or polycarboxylic acids or sulphonic acids, and mineral acids providedthat they are capable of salifying the amino group of compound XIa, forinstance fumaric acid, maleic acid, lactic acid, salicylic acid,succinic acid, glycolic acid, tartaric acid, acetic acid, citric acid,formic acid, benzoic acid, malonic acid, oxalic acid, hydrochloric acid,hydrobromic acid, sulphuric acid, nitric acid, perchloric acid,phosphoric acid, p-toluenesulphonic acid, methanesulphonic acid,2-naphthalenesulphonic acid, benzenesulphonic acid and4-chlorobenzenesulphonic acid, preferably oxalic acid, succinic acid,maleic acid, methanesulphonic acid, 4-chlorobenzenesulphonic acid andhydrochloric acid, and even more preferably oxalic acid.

The amount of acid used is at least equal to the stoichiometric amount.

The precipitation of the salt of compound XIa may optionally be promotedvia conventional techniques such as cooling of the solution, initiationby addition of crystals of the same salt, or other methods that are wellknown to those skilled in the art.

The precipitated salt of the compound of formula XIa is generallyrecovered by filtration, centrifugation or decantation, preferably byfiltration, although other conventional methods known to those skilledin the art may also be used.

The filtration is formed using standard filtration means such as pressfilters, static filters, centrifuges and other standard industrialfiltration techniques.

The salt of compound XIa with the said organic or mineral acidsconstitutes a further subject of the present invention. The said saltmay be obtained by salification of compound XIa with fumaric acid,maleic acid, lactic acid, salicylic acid, succinic acid, glycolic acid,tartaric acid, acetic acid, citric acid, formic acid, benzoic acid,malonic acid, oxalic acid, hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, perchloric acid, phosphoric acid,p-toluenesulphonic acid, methanesulphonic acid, 2-naphthalenesulphonicacid, benzenesulphonic acid or 4-chlorobenzenesulphonic acid, preferablywith oxalic acid, succinic acid, maleic acid, methanesulphonic acid,4-chlorobenzenesulphonic acid or hydrochloric acid, and even morepreferably with oxalic acid.

The salt of compound XIa isolated as described above may be furtherpurified, for example by crystallization, or subjected to a standardbasic treatment to give compound XIa as free base, or, preferably, useddirectly in the subsequent reaction.

The compound XIa thus obtained generally has a very high purity, whichis reflected in a further advantage of the present invention over theprocesses of the prior art.

Specifically, by using the intermediate XIa of the present process inthe subsequent reductive passage, it is possible to obtain emtricitabineIa in a purity that allows its direct crystallization, as free base,thus making it unnecessary to perform steps ofsalification/crystallization/liberation of the base—as described forlamivudine in U.S. Pat. No. 6,051,709—or even making it unnecessary topurify the emtricitabine base by chromatography, as takes place in U.S.Pat. No. 5,696,254 (Example 21).

This last aspect of the process of the invention is particularlyadvantageous when it is considered that final release of theemtricitabine salt suggested by the art can cause the formation oforganic or mineral salts that are difficult to remove, for instancetriethylamine hydrochloride, which may then contaminate the activeprinciple. In this event, since the process concerns a medicinalproduct, it will then be necessary to perform further purification stepsto ensure the required high standard of purity, with all the entailingoperating and economic drawbacks.

However, in the present process, emtricitabine Ia, obtained by thefollowing reductive reaction:

is isolated as a crude product, under the standard conditions forworking up reductive reactions of this type, and is subsequentlycrystallized from suitable solvents such as methylene chloride, alcoholssuch as isopropanol or esters such as ethyl acetate or isopropylacetate, or mixtures thereof, for instance methanol and isopropylacetate, preferably from a mixture of methanol and isopropyl acetate,thus directly forming emtricitabine in high purity and with good yields.

This final reduction reaction may be performed, for example, asdescribed in U.S. Pat. No. 5,696,254 (Example 21) or in U.S. Pat. No.6,051,709 (Example 1c) or under analogous conditions known to thoseskilled in the art.

In the present invention, the said reduction is preferably performed byreleasing in situ the base of compound XIa from its isolated salt(one-pot reaction) via a standard basic treatment.

It is obvious to those skilled in the art that the process that is thesubject of the present invention, in all its variants, will also beapplicable to the preparation of the other cis isomer of emtricitabine,i.e. the (2S, 5R) compound Ib. In this case, the salification reactionwill be performed on the key intermediate of formula XId, which in turnmay be obtained via the same reactions discussed above for thepreparation of emtricitabine, except that the chiral auxiliary will berepresented by D-menthol.

In one preferred embodiment of the present process, compound V(2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,5R)-5-hydroxy[1,3]-oxathiolane-2-carboxylate) is converted into thecorresponding chloro derivative (VI, LG=Cl) and then reacted withsilylated 5-fluorocytosine (III) until the condensation reaction iscomplete.

Alternatively, compound X (2S-isopropyl-5R-methyl-1R-cyclohexyl (2R,5S)-5-acetoxy-[1,3]oxathiolane-2-carboxylate) is reacted with silylated5-fluorocytosine (III) in the presence of Lewis acids until thecondensation reaction is complete.

The crude product (XIa) obtained after working up the reaction isdissolved in methanol and salified with oxalic acid. The oxalatecompound XIa is separated out by filtration and used in the same form inthe subsequent reduction reaction with sodium borohydride. After workingup the reaction, a crude product is obtained, which, by crystallizationfrom methanol/isopropyl acetate, gives emtricitabine (Ia) directly.

A number of practical examples will now be given to illustrate thepresent invention more clearly.

EXPERIMENTAL SECTION EXAMPLE 1 2′S-Isopropyl-5′R-methyl-1′R-cyclohexyl(2R,5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylateoxalate

-   -   A. Thionyl chloride (24.5 g) was added slowly at about 8° C. to        a solution of 2′S-isopropyl-5′R-methyl-1′R-cyclohexyl esther        (2R, 5R)-5-hydroxy[1,3]oxathiolane-2-carboxylate (V) (50 g) and        methanesulphonic acid (0.2 ml) in methylene chloride (500 ml)        and dimethylformamide (15 ml).        -   The reaction mixture was stirred at 15° C. for about 4 hours            and a portion of the methylene chloride (about 350 ml) was            then distilled off under vacuum. More methylene chloride            (150 ml) was added and some of this (about 50 ml) was            evaporated off under vacuum.    -   B. In another flask, a mixture of 5-fluorocytosine (20 g),        hexamethyldisilazane (43 ml) and methanesulphonic acid (0.2 ml)        in toluene (75 ml) was refluxed for about 3 hours. The reaction        mixture was then distilled under vacuum down to a residue,        methylene chloride (about 100 ml) was then added and the mixture        was re-evaporated under vacuum. The residue was then redissolved        in methylene chloride (250 ml) and triethylamine (28 ml) was        added dropwise at 20-25° C. This 5-fluorocytosine silylate        mixture was heated to reflux and the solution prepared in point        A was slowly added dropwise over 2-3 hours while maintaining the        reflux. The reaction mixture thus obtained was refluxed for        about 18 hours and then cooled to 20-25° C. and water (150 ml)        was added.        -   The aqueous phase was separated out and the organic phase            was washed 5 times with acidified water (5×150 ml) and then            with water (150 ml). The solvent was evaporated off under            vacuum, the residue was dissolved in methanol (220 ml) and            oxalic acid dihydrate (20 g) was added to the solution. The            suspension thus obtained was stirred at 20-25° C. for 3            hours and the solid was then filtered off, washed with            methanol (30 ml) and dried to give 31.5 g of            2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,            5S)-5-(4-amino-5-fluoro-2-oxo-2pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate            oxalate (m.p. 152-153° C.).

The following salts were also prepared in a similar manner:

-   -   2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,        5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate        maleate (m.p. 155-156° C.).    -   2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,        5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate        succinate (m.p. 196-197° C.).    -   2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,        5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate        methanesulphonate (m.p. 183-184° C.).    -   2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,        5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate        4-chlorobenzenesulphonate (m.p. 212-213° C.).    -   2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,        5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate        hydrochloride (m.p. 208-209° C.).

(2R,5S)-4-Amino-5-fluoro-1-(2-hydroxymethyl[1,3]oxathiolan-5-yl)-1H-pyrimidin-2-one(emtricitabine)

2′S-Isopropyl-5′R-methyl-1′R-cyclohexyl (2R,5S)-5-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylate(31.5 g) was suspended in a mixture of tetrahydrofuran (140 ml),methanol (28 ml) and water (46.6 g). Potassium bicarbonate (6.5 g) andpotassium hydrogen phosphate (14 g) were added. The suspension wascooled to 0-5° C. and a solution of sodium borohydride (11.2 g) and 30%sodium hydroxide (1.1 ml) in water (112 ml) was added slowly over about2-3 hours. The reaction mixture was then stirred at 20-25° C. for 1hour. The pH was then brought to 4.0 with 37% hydrochloric acid and theorganic solvents were then evaporated off under vacuum. The remainingaqueous phase was extracted three times with toluene (3×70 ml) and thepH of the aqueous solution was then brought to 7.3-7.4 with 30% sodiumhydroxide and the water was evaporated off under vacuum. The residue wastaken up in isopropanol (100 ml) and evaporated under vacuum, and thentaken up again in isopropanol (200 ml). The mineral salts were filteredoff and the filtrate was evaporated under vacuum. The crude product wasdissolved in methanol (15 ml) and crystallized by adding isopropylacetate (35 ml). The suspension was stirred overnight at 20° C. and thesolid was filtered off and dried to give 5 g of emtricitabine.

EXAMPLE 2 2′S-Isopropyl-5′R-methyl-1′R-cyclohexyl(2R,5S)-5-(4-amino-5-fluoro-2-oxo-2-H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylateoxalate

A mixture of 5-fluorocytosine (3.8 g), hexamethyldisilazane (8.1 ml) andmethanesulphonic acid (0.02 ml) in toluene (27 ml) was refluxed forabout 3 hours. The reaction mixture was then distilled to dryness undervacuum and methylene chloride (about 15 ml) was then added andre-evaporated under vacuum. The residue was then redissolved inmethylene chloride (30 ml) and a solution of2S-isopropyl-5R-methyl-1R-cyclohexyl (2R,5S)-5-acetoxy[1,3]oxathiolane-2-carboxylate (12.1 g) in methylenechloride (30 ml) was added. Trimethyliodosilane (5.3 ml) was addedslowly and the reaction mixture was stirred at room temperature forabout 2 hours. The mixture was diluted with methylene chloride (400 ml)and the aqueous phase was washed with saturated sodium metabisulphitesolution (100 ml) and then with water (100 ml) and with saturated sodiumchloride solution (100 ml).

The organic phase was evaporated off and the residue dissolved inmethanol (100 ml) and oxalic acid dihydrate (4.7 g) was added. Thesuspension thus obtained was stirred at 20-25° C. for 3 hours and thesolid was then filtered off, washed with methanol (10 ml) and dried togive 9.2 g of 2′S-isopropyl-5′R-methyl-1′R-cyclohexyl (2R,5S)-5-(4-amino-5-fluoro-2-oxo-2-H-pyrimidin-1-yl)[1,3]oxathiolane-2-carboxylateoxalate (m.p. 152-153° C.).

1. Process for preparing emtricitabine of formula (Ia)

comprising the salification reaction of an intermediate compound offormula (XIa)

dissolved in a suitable solvent, by treating the intermediate compoundof formula (XIa) with an organic or mineral acid to give thecorresponding salt, wherein the corresponding salt is in an isolablesolid form.
 2. The process of claim 1, wherein the solvent is selectedfrom the group consisting of alcohols, hydrocarbons, esters, ethers,chlorinated solvents, and mixtures thereof.
 3. The process of claim 2,wherein the solvent is selected from the group consisting of methanol,ethanol, isopropanol, toluene, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate, isobutyl acetate, tetrahydrofuran, dioxane,methylene chloride, and mixtures thereof.
 4. The process of claim 1,wherein said organic or mineral acid is selected from the groupconsisting of fumaric acid, maleic acid, lactic acid, salicylic acid,succinic acid, glycolic acid, tartaric acid, acetic acid, citric acid,formic acid, benzoic acid, malonic acid, oxalic acid, hydrochloric acid,hydrobromic acid, sulphuric acid, nitric acid, perchloric acid,phosphoric acid, p-toluenesulphonic acid, methanesulphonic acid,2-naph-thalenesulphonic acid, benzenesulphonic acid,4-chlorobenzenesulphonic acid, and mixtures thereof.
 5. The process ofclaim 4, wherein said organic or mineral acid is selected from the groupconsisting of oxalic acid, succinic acid, maleic acid, methanesulphonicacid, 4-chlorobenzene-sulphonic acid, hydrochloric acid, and mixturesthereof.
 6. The process of claim 1, further comprising isolating saidcorresponding salt by filtration.
 7. Process for preparing the compoundof formula (Ib)

comprising the salification reaction of an intermediate compound offormula (XId)

dissolved in a suitable solvent, by treating said intermediate compoundof formula (XId) with organic or mineral acids to give the correspondingsalt, which is insoluble in the said solvent, in readily isolable solidform.
 8. The process of claim 2, wherein the solvent is from the groupconsisting of methanol, isopropanol, ethyl acetate, and mixturesthereof.
 9. The process of claim 4, wherein said organic or mineral acidis oxalic acid.